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Inhibition of the Nonessential Neurovirulence Gene of Herpes Simplex Virus Type 1 Using RNA Interference
Get PDFHerpes simplex virus type 1 (HSV-1) is a common pathogen that causes recurrent and latent infections in humans. The nonessential neurovirulence gene γ134.5 prevents cellular responses to an infection in differentiated host cells. The deletion of this gene makes HSV-1 conditionally replicative. Thereby most of the HSV-1 vectors and oncolytic viruses carry this deletion. The objective of this study was to assess whether targeting γ134.5 using RNA interference would be antiviral or gene-specific. The effects of six siRNAs targeting γ134.5 were studied in vitro. The cellular viability, antiviral efficacy, γ134.5 gene expression, and host responses were assessed. Three cell lines were used – U373MG representing neuronal cells, HCE representing epithelial cells, and Vero cells (non-human primate kidney). The viruses used were the recombinant wild type-like HSV-1(17+)LoxPmCMVGFP and the HSV vector backbone H1052. The γ134.5 siRNAs were well tolerated in U373MG and HCE cells. The γ134.5 gene expression of the wild type–like virus was inhibited in U373MG cells. Some γ134.5 siRNA treatments induced a reduction in viral shedding whilst others an increase. This was correlated with the innate immunity, where the samples with an increase in viral shedding had a reduction in cellular responses. The successful inhibition of γ134.5 in U373MG cells shown in this study could be further developed into a new method for vector production and selection in vitro, or to new in vivo infection models with protection from severe infections, when using wild type-like viruses
Decorin-expressing oncolytic herpes simplex virus vector for novel cancer therapy
No full textCancer is still one of the deadliest diseases, although great efforts have beenmade to discover and develop anti-cancer drugs. Therefore, new strategies for cancer treatment need to be developed, and one promising area of research is oncolytic herpes simplex vectors. These vectors have an advantage over conventional treatments due to being less toxic and thereby safer. Furthermore, they can be used in combination with conventional therapies. By the removal of nonessential genes that are responsible for virulence, the vectors retain the ability to infect malignant cells while not harming healthy cells through selective replication. Such vectors have already shown success clinically. In addition, they can also carry transgenes to further suppress tumors, such as immunological or restored dysfunctional genes.
Decorin (DCN) is an extracellular proteoglycan that is expressed in most connective tissues, which is essential for maintaining the normal tissue functions, such as wound healing. It has been noted to be under-expressed in many cancers, and restoration of DCN has tumor-suppressive properties. Due to its important functions in the extracellular matrix, it is a promising transgene for viral vectors, as adjacent cells, which are not directly transduced by the vector, will be affected.
This work is a proof-of-concept study in which the hypothesis that expression of the DCN transgene using an oncolytic herpes simplex vector isa viable strategy for the treatment of cancer was investigated. In this study, the construction and characterization of the DCN-expressing herpes simplex vector was tested, its oncolytic efficacy in vitro was tested, the pulmonary delivery of a marker vector in vivo was tested, and the anti-angiogenic activity of the vector in a chorioallantoic membrane tumor xenograft model was examined.
The results presented in this thesis show that the vector design was successful, as DCN expression was induced by the vector after transduction. Furthermore, expression of the DCN transgene improved the oncolytic efficacy of the herpes simplex vector in vitro. The results also show that pulmonary delivery of marker vectors in vivo is possible by intranasal administration, and that DCN expression reduces angiogenesis in xenografted tumors.
This proof-of-concept thesis concludes that delivery of DCN using an oncolytic herpes simplex vector is a viable and novel strategy for treating cancer. In vivo studies should be conducted to further gain data on its efficacy.Cancer kvarstår som en av de dödligaste sjukdomarna även efter en massivsatsning inom läkemedelsutveckling mot cancer. Det finns ett behov att utveckla nya strategier för att bota cancer, och herpes simplex vektorer är ett lovande forskningsområde, då de orsakar få biverkningar, till skillnad från de konventionella läkemedlen. De kan användas i kombination med andra terapier. Genom att radera icke-essentiella genprodukter som orsakar virulens kan vektorerna behålla sin egenskap att infektera tumörer, men kan inte skada friska celler. Sådana vektorer har redan sett klinisk framgång. Dessutom kan de bära på transgener som tillsvidare hindrar tumörens växt, så som immunologiska eller återställda dysfunktionella gener.
Dekorin är ett extracellulärt proteoglykan som är uttryckt i de flestabindväv, och som är essentiellt för normala funktioner såsom sårläkning. Det har märkts att cancer oftast underuttrycker dekorin och att dekorinets återställning kväver tumörer. På grund av dess extracellulära funktioner är dekorin en lovande transgen för virala vektorer, då närliggande celler sominte är direkt transducerade av vektorn blir påverkade.
Denna avhandling är ett koncepttest som utreder om uttrycket av transgent dekorin med hjälp av en onkolytisk herpes simplex vektor är en framkomlig strategi för bot av cancer. Denna avhandling detaljerar konstruktionen av en dekorinuttryckande herpes simplex vektor, dess karakterisering, dess onkolytiska verkan in vitro, pulmonär leverans av markörvektorer in vivo, och angiogeneshämmande verkan av den nya vektorn i tumörxenograft i chorioallantoismembranmodeller.
Resultaten som framförs i denna avhandling bevisar att konstruktionen av den nya vektorn var framgångsrik, att dekorinuttrycket transduceras i ochmed infektering med vektorn, att dekorinuttryck förbättrar onkolytiska verkan in vitro, att pulmonär leverans av markörvektorer är genomförbart med intranasal administration, och att dekorinuttryck inhiberar angiogenes i tumörxenograft.
Denna koncepttestavhandling kommer till slutsatsen att dekorinuttryckning med en onkolytisk herpes simplex vektor är en möjlig strategi för att utveckla nya cancerterapier, och att framtida in vivo experiment bör anföras för att erhålla mer data om vektorns antitumöra verkan.navigointi mahdollist
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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